Cognitive impairment can reduce the capacity of individuals to learn, remember, communicate, socialize, problem solve, and/or function independently. It may be due to a neurodevelopmental or neurodegenerative disorder caused by genetic and/or environmental factors, or it may be an acquired condition.
Neurodevelopmental disorders that manifest themselves in cognitive impairment include, for example, Down syndrome, phenylketonuria, neurofibromatosis type 1, maple syrup urine disease, fetal alcohol syndrome, Rett syndrome, neonatal malnutrition, fragile X syndrome, and autism spectrum disorders. Neurodevelopmental disorders affect 2-3% of the population in the industrialized world. The most common neurodevelopmental disorder with a known genetic etiology is Down syndrome, which occurs in approximately 1/700-1,000 live births, and is caused by total or partial triplication of chromosome 21 (Hsa21), resulting in the overexpression of approximately 300-400 genes.
Neurodegenerative disorders that manifest themselves in cognitive impairment include, for example, Parkinson's disease, Huntington's disease, vascular dementia, idiopathic dementia, and Alzheimer's disease. Alzheimer's disease alone affects more than 25 million people worldwide and more than 5 million Americans, and is the 7th leading cause of death in the United States. The risk of developing a neurodegenerative disorder generally increases with age.
In addition to cognitive impairment caused by neurodevelopmental or neurodegenerative disorders, acquired conditions may also impair cognitive function in normal subjects. Such acquired conditions include “jet” lag, circadian rhythm disruptions, sleep apnea, and sleep disturbances.
Cognitive function is generated by neuronal networks that exhibit an appropriate balance of inhibition and excitation. Although excitation is the primary way of information transfer between various brain regions, inhibition plays an equally important role in many neuronal networks by being responsible, for example, for bursting and oscillatory activity. Imbalanced excitation and inhibition in neuronal networks can result in reduced brain function and/or pathology. For example, excessive excitation can produce epilepsy or seizures, and excessive inhibition can lead to cognitive deficits or sedation.
A major inhibitory neurotransmitter in the mammalian central nervous system is γ-aminobutyric acid (GABA). One of the receptors for GABA signaling in the mammalian central nervous system is the GABAA receptor, which is a heteropentameric, ligand-gated anion channel. Binding of GABA to the GABAA receptor results in increased influx of chloride ions across the post-synaptic membrane. Such increased chloride ion conductance produces inhibition of depolarization, or even hyperpolarization, of the post-synaptic membrane, and thus an inhibition of neuronal firing of the postsynaptic neuron.
Excessive inhibition mediated by the GABAA receptor has been documented in a mouse model of Down syndrome, namely in the Ts65Dn mouse. The Ts65Dn mouse is trisomic for about 100 genes on mouse chromosome 16 (Mmu16) that are homologous to genes on Hsa21 in human Down syndrome patients. Ts65Dn mice exhibit learning and memory deficits and corresponding anatomical and physiological abnormalities that are similar to those found in human Down syndrome patients. Interestingly, in the hippocampus of Ts65Dn mice excessive activity of inhibitory neurons has been shown, concomitant with deficits in hippocampal long-term potentiation (LTP) induction.
Interestingly, hippocampal LTP induction and cognitive function in Ts65Dn mice has been shown to improve in a long-lasting manner by the short-term administration of low doses of compounds such as pentylenetetrazole (PTZ), bilobalide (BB), and picrotoxin (PTX) that reduce inhibition mediated by the GABAA receptor. See, e.g., Fernandez et al., 2007, Nat. Neurosci. 10: 411-3; Rueda et al., 2008, Neurosci. Lett. 433: 22-7; Costa & Grybko, 2005, Neurosci. Lett. 382: 317-22; Kleschevnikov et al., 2004, J. Neurosci. 24: 8153-60; U.S. Patent App. Pub. No. 2008/0009475.
Numerous diseases exhibit circadian variation in progression, symptoms, and risk. The chronobiology of symptom severity has been confirmed for hypertension, cardiovascular disease (heart attack), stroke, arthritis, asthma, gastrointestinal disorders, epilepsy, multiple sclerosis, and other disorders. Circadian rhythm sensitive dosing aims to target drugs to the portions of the circadian cycle during which disease progression, symptoms, risk, or treatment efficacy are highest. No such chronotherapeutic strategy for cognitive impairment has been described.
Proper memory function requires encoding a memory during learning, consolidation of that recently acquired memory to long-term memory in the hours and days that follow, and retrieval of the learned content. Consolidation of memories occurs primarily during sleep. See, e.g., Stickgold, 2005, Nature 437(7063): 1272-8. Sleep is composed of a repeating cycle of phases that can be identified by differences in the brain and body, including variation in brain rhythms, heart rate, and movement. The sleep cycle includes rapid eye movement (REM) sleep and non-REM sleep that is divided into light sleep and deep sleep. Deep or ‘slow-wave’ sleep (SWS) is important for consolidating long-term memories. See, e.g., Diekelmann and Born, 2010, Nat. Rev. Neurosci. 11(2): 114-26). During the course of a period of sleep—for instance a night of sleep in a human—the proportion of time spent in the various phases of sleep generally changes. In particular, REM portions of the cycle become longer and non-REM portions of the cycle become shorter during the course of a night of sleep.
Recent discoveries in the fields of neurobiology, psychology, and sleep research have characterized the important relationship between sleep and memory. Sleep is required for normal memory consolidation and the amount of high-quality sleep can impact the level of cognitive function. In people, intensive periods of learning cause an increase in the amount of SWS the following night. See Eschenko et al., 2008, Learn. Mem. 15(4): 222-8. This suggests that SWS is required for memories to be consolidated. See Ellenbogen et al, 2006, Curr. Opin. Neurobiol. 16(6): 716-22. In rodents, patterns of activity of neurons in the hippocampus, a key brain region for memory, occur in a predictable and sequential pattern when a rodent explores a maze or other environment. See, e.g., Davidson et al., 2009, Neuron 63(4): 497-507; Wilson and McNaughton, 1994, Science 265(5172): 676-9; Wilson and McNaughton, 1993, Science 261(5124): 1055-8. The spatial memory represented by this experience is thought to be consolidated during sleep. Electrical recordings of neuronal activity during SWS have identified the ‘replay’ of patterns of neural activity observed during previous experience. See, e.g., Euston et al., 2007, Science 318(5853): 1147-50; Ji and Wilson, 2007, Nat. Neurosci. 10(1): 100-7; Lee and Wilson, 2002, Neuron 36(6): 1183-94; Louie and Wilson. 2001, Neuron 29(1): 145-56; Shen et al., 1998, J. Sleep Res. 7(Suppl 1): 6-16. This suggests that replay is an important mechanism for memory consolidation. Interrupting replay during sleep disrupts memory formation. See Ego-Stengel and Wilson, 2010, Hippocampus 20(1): 1-10.
Current drug therapies for cognitive impairment are at best symptomatic and supportive therapies. Consequently, there is an unmet medical need for drugs and methods for treating or preventing cognitive deficits, a need that is steadily increasing in our ageing Western civilization. Such treatments might also benefit normal individuals in improving cognitive functions.